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FDA To Advisors: What If One-Time Gene Therapy Needs Extra Doses?

In the run-up to a key vote on an experimental gene therapy, the FDA raised no major flags about the drug’s track record but said its long-term effect remains an open question.

That question should receive a thorough airing Thursday, when a meeting of FDA outside advisors will weigh a recommendation of the one-shot gene therapy, which is meant to cure a rare eye disease that leads inevitably to blindness.

The therapy, developed by Philadelphia-based Spark Therapeutics (NASDAQ: ONCE), is called voretigene neparvovec (Luxturna). If approved—the FDA’s approval deadline is January 18—the Spark drug would be the first medicine to receive a U.S. nod to replace a faulty gene with a working version. Last month, the FDA approved a so-called CAR-T treatment for kids with leukemia that consists of the patients’ own immune cells genetically boosted to be better cancer fighters. Some observers hailed the medicine, branded as Kymriah, as the first gene therapy to be approved in the U.S.

In documents released today, FDA scientists asked the committee to consider several questions before it votes yes or no on a recommendation Thursday. (Advisory committee votes are not binding, but the agency usually follows their recommendations.)

One question is whether the drug, injected into the eye, should be given to a patient more than once. “It is unclear if the effect decays over time, as longer term follow up data is not available,” the agency writes. “Repeat administration of voretigene neparvovec in any eye was not evaluated in the clinical studies. Therefore, there are no clinical data that address the potential benefits and risks of repeat administration of voretigene neparvovec.”

Spark says all participants in the clinical studies of voretigene neparvovec will be followed for 15 years, with annual check-ups, from the time of their injection.

The question of potential repeat injections is relevant not only because gene therapy represents uncharted medical territory, but also because the healthcare system, and society at large, is grappling with the cost of expensive medicines. And gene therapy will be expensive. Kymriah is $475,000 (with caveats) for a one-time dose.

If a drug meant as a one-time cure turns out to require additional shots, it could change the pricing calculus and the willingness of insurers to cover it. A high price is also inevitable because Spark will have relatively few chances to recoup its investment.

Between 1,000 and 3,000 patients in the U.S. have the genetic mutation that the Spark therapy aims to fix by injecting billions of copies of viruses, engineered to carry a working copy of the RPE65 gene, into their eyes. Without the RPE65 protein, the eye sustains damage to key cells, and the eye’s photoreceptors lose their ability to turn light into electrical signals. The photoreceptors eventually die.

For Spark’s voretigene neparvovec, the main body of data to evaluate comes from a 31-patient study. Participants were assigned randomly to receive the treatment or nothing at all. (The study was open label: Those not receiving the drug were aware of the situation.)

Two people dropped out before the injections, which left 29 people—20 receiving voretigene neparvovec, nine in the control arm—to power the study. The control group was allowed to “cross over” and receive the gene therapy after one year.

How much that small body of evidence concerns the FDA’s outside advisors or its own reviewers remains to be seen. But the FDA’s document acknowledged that after one year the main outcome, a boost in vision at lower light levels, for patients receiving the gene therapy compared to those in the control arm were “significantly different.” The nine control patients who crossed over to receive voretigene neparvovec showed the same one-year improvement as the original group.

Spark’s own documents called the overall safety risks “acceptable” and noted that even the serious side effects quickly resolved themselves. The FDA overview was less effusive, noting that the injection procedure’s safety risks meant that only patients with significant vision loss were allowed to enter the Spark studies.

That condition, plus the fact that voretigene neparvovec had a better effect on patients with less advanced disease, adds a layer of intrigue about the subpopulation of patients who might be eligible to receive the treatment, if eventually approved.

Alex Lash is Xconomy's National Biotech Editor. He is based in San Francisco. Follow @alexlash